The overall scientific goal of this project is to understand the role of desmoplakin (DSP), a desmosomal protein, in the development of Idiopathic Pulmonary Fibrosis (IPF). IPF, the most common idiopathic interstitial pneumonia (IIP), is a complex disease caused by a number of gene variants in combination with specific environmental exposures. Recently, a genome-wide association study (GWAS) identified seven novel loci that are associated with fibrotic IIP, including multiple SNPs in desmoplakin (DSP) at 6p24. DSP should be studied in IPF because: (1) the IIP-associated DSP variants are genetically restricted since these variants are bounded by recombination hotspots, (2) expression of DSP differed in IIP patients and also differed by DSP genotype at rs2076295, (3) DSP is expressed by airway epithelia, and (4) DSP is a strong biological candidate. DSP is an intracellular component of the desmosome, a structure that links cells and forms dynamic structures with other proteins to tether the cytoskeleton to the cell membrane and are abundant in cells undergoing constant physical stress (such as the heart, skin, and airway). As such DSP may be particularly important in regions of the lung that experience constant mechanical stress, such as the peripheral and basilar segments, which are affected preferentially in IPF. Impairment of desmosomes or their accompanying structures leads to disruption in epithelial homeostasis, as has been shown in other organ systems including the heart. These observations suggest that epithelial desmosomal dysfunction may disrupt homeostasis and repair, contributing to an impaired response to injury that may prove relevant to IPF. This proposal's approach is to identify individuals with a significant DSP variant (rs2076295) in humans associated with IPF and to obtain nasal epithelial cells from them. Using in vitro techniques, I will determine how this variant alters DSP expression and function in vitro in basal and stressed states. I hypothesize that the rs2076295 variant in DSP impairs baseline epithelial function and the response of airway epithelia to injurious exposures and to mechanical stress. This will be pursued in the following aims: (1) Determine the effect of DSP variant rs2076295 on expression and function of DSP in vitro as well as on levels of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in basal and stressed states; (2) Determine the effect of the DSP variant on epithelial response to mechanical stress and on ER stress and UPR. These investigations into the potential role of DSP in IPF may lead to new therapeutic targets for a disease that has no effective therapies at this time.